WO2016106266A1 - Antagonistes des récepteurs tgfβ - Google Patents

Antagonistes des récepteurs tgfβ Download PDF

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Publication number
WO2016106266A1
WO2016106266A1 PCT/US2015/067252 US2015067252W WO2016106266A1 WO 2016106266 A1 WO2016106266 A1 WO 2016106266A1 US 2015067252 W US2015067252 W US 2015067252W WO 2016106266 A1 WO2016106266 A1 WO 2016106266A1
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Prior art keywords
alkyl
hydrogen
pyridin
halogen
independently
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PCT/US2015/067252
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English (en)
Inventor
Brian E. Fink
Yufen Zhao
Robert M. Borzilleri
Liping Zhang
Kyoung S. Kim
Muthoni G. Kamau
Andrew J. Tebben
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Bristol-Myers Squibb Company
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Priority to CN201580076649.4A priority Critical patent/CN107257798A/zh
Priority to EP15823892.3A priority patent/EP3237415A1/fr
Priority to JP2017552007A priority patent/JP2018501315A/ja
Publication of WO2016106266A1 publication Critical patent/WO2016106266A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/582—Recycling of unreacted starting or intermediate materials

Definitions

  • TGF The active form of TGF is a dimer that signals through the formation of a membrane bound heterotetramer composed of the serine threonine type 1 and type 2 receptors, TGF R-l (ALK5) and TGF R-2, respectively.
  • TGF R-l ALK5
  • TGF R-2 TGF R-2
  • the type 2 constitutively activated receptors phosphorylate the type 1 receptors in the glycine and serine rich "GS region" activating a signaling cascade through the intracellular signaling effector molecules, Smad2 or Smad3.
  • TGF R-l phosphorylates the receptor Smad2 and/or Smad3 (RSmads) that form a complex with Smad4 (Shi and Massague, Cell 2003, 113:685-700).
  • R 2 is independently one or more hydrogen, -CD3, OCD3, halogen, -CF3, -CHF2, - CN, (Ci-C 6 )alkyl, (Ci-C 6 )alkoxy or -SO2 (Ci-C 6 )alkyl;
  • R 5 and R 6 can be taken together with the nitrogen atom to which they are attached to form a 5-7 membered heterocyclo ring;
  • n 0, 1, 2, 3, or 4;
  • R is AA, or a heterocylic or heterobicyclic group substituted with 0-4 R 2 ;
  • X 1 , X 2 , X 3 and X 4 are independently -CR 4 or -N-, wherein at least one is -N-;
  • R 1 is hydrogen, (Ci-C 6 )alkyl, (C 3 -C 8 )cycloalkyl, -CONHR 9 , -COOR 9 , -COR 9 or - SO2R 9 , any of which except the hydrogen is substituted with 0-3 R x ;
  • W is hydrogen, halogen, -OH, (Ci-C 3 )alkyl, halo(Ci-C 3 )alkyl, hydroxy(Ci- C 3 )alkyl, -amino(Ci-C3)alkyl, -NHCOOH, or -CN;
  • R 7 is independently one or more hydrogen, halogen, halo(Ci-C6)alkyl or -CN;
  • R 8 is hydrogen, (Ci-C 6 )alkyl, (C3-C 8 )cycloalkyl, -CONHR 9 , -COOR 9 , -COR 9 or -
  • R x is hydrogen, halogen, -OH, halo(Ci-C3)alkyl, hydroxy(Ci-C3)alkyl, -amino(Ci- C 3 )alkyl, or -CN;
  • R 2 is independently one or more hydrogen, -CD3, OCD3, halogen, -CF3, -CHF2, - CN, (Ci-C 3 )alkyl, (Ci-C 3 )alkoxy or -SO2 (Ci-C3)alkyl;
  • R 2 is independently one or more hydrogen, -CD3, OCD3, halogen, -CF3, -CHF2, - CN, (Ci-C3)alkyl, (Ci-C 3 )alkoxy or -SO2 (Ci-C3)alkyl;
  • R 5 and R 6 are independently hydrogen, -C(0)alkyl or (Ci-C3)alkyl; or
  • R 3 is independently one or more hydrogen, CD3, OCD3, halogen, -CN, (Ci- C 6 )alkyl, (C2-C 6 )alkenyl, (Ci-C 6 )alkoxy, (C3-C 8 )cycloalkyl, hydroxy(Ci-C3)alkyl, (Ci- C6)alkylamino-, (Ci-C6)alkylamino(Ci-C6)alkyl, 5-6 membered heteroaryl, heterocyclyl, O-heterocyclyl, -NR 5 R 6 , -CONR 5 R 6 , -COOR 4 , -COR 4 , -SO2R 4 , -CHCF2COOCH2OH or - CHCF2CONH2, any of which except the hydrogen is substituted with 0-4 R y ;
  • R 1 is hydrogen, (Ci-C 3 )alkyl, (C3-C 6 )cycloalkyl, -CONHR 9 , -COOR 9 , -COR 9 or - SO2R 9 , any of which except the hydrogen is substituted with 0-3 R x ;
  • R 3 is independently one or more hydrogen, CD3, OCD3, halogen, -CN, (Ci- C 3 )alkyl, (C2-C 6 )alkenyl, (Ci-C 3 )alkoxy, (C3-C 8 )cycloalkyl, hydroxy(Ci-C3)alkyl, (Ci- C3)alkylamino-, (Ci-C3)alkylamino(Ci-C3)alkyl, 5-6 membered heteroaryl, heterocyclyl, O-heterocyclyl, -NR 5 R 6 , -CONR 5 R 6 , -COOR 4 , -COR 4 , -SO2R 4 , -CHCF2COOCH2OH or - CHCF2CONH2, any of which except the hydrogen is substituted with 0-4 R y ;
  • R 9 is hydrogen, (Ci-C6)alkyl, (C 3 -C8)cycloalkyl, heterocyclylalkyl-,
  • R x is hydrogen, halogen, -OH, halo(Ci-C 3 )alkyl, hydroxy(Ci-C 3 )alkyl, -amino(Ci- C 3 )alkyl, or -CN;
  • R 7 is independently one or more hydrogen, halogen, halo(Ci-C3)alkyl or -CN;
  • R 1 is -COR 9 ;
  • R 7 is independently one or more hydrogen, halogen, halo(Ci-C3)alkyl or -CN;
  • n 0, 1 or 2;
  • the compounds of formula (I) of the invention are TGFBR antagonists and have potential utility in the treatment of diseases and conditions for which a TGFBR antagonist is indicated.
  • a method for treatment of a chronic autoimmune and/or inflammatory condition in a subject in need thereof which comprises administering a therapeutically effective amount of one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof.
  • Types of cancers that may be treated with the compounds of this invention include, but are not limited to, brain cancers, skin cancers, bladder cancers, ovarian cancers, breast cancers, gastric cancers, pancreatic cancers, prostate cancers, colon cancers, blood cancers, lung cancers and bone cancers.
  • Examples of such cancer types include neuroblastoma, intestine carcinoma such as rectum carcinoma, colon carcinoma, familiar adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, esophageal carcinoma, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tong carcinoma, salivary gland carcinoma, gastric carcinoma,
  • the compound(s) of the invention are sequentially administered prior to administration of the immuno-oncology agent. In another aspect, compound(s) of the invention are administered concurrently with the immunology-oncology agent. In yet another aspect, compound(s) of the invention are sequentially administered after administration of the immuno-oncology agent.
  • compounds of the invention may be co-formulated with an immuno-oncology agent.
  • the immuno-oncology agent is (i) an agonist of a stimulatory (including a co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including a co- inhibitory) signal on T cells, both of which result in amplifying antigen-specific T cell responses (often referred to as immune checkpoint regulators).
  • the immuno-oncology agent is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF- ⁇ , VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation, for stimulating an immune response.
  • a cytokine that inhibits T cell activation e.g., IL-6, IL-10, TGF- ⁇ , VEGF, and other immunosuppressive cytokines
  • a cytokine that stimulates T cell activation for stimulating an immune response.
  • agents that can be combined with compounds of the invention for the treatment of cancer include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells.
  • compounds of the invention can be combined with antagonists of KIR, such as lirilumab.
  • compounds of the invention can be used with one or more of agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that increase systemically the frequency of anti-tumor T cells, agents that overcome distinct immune suppressive pathways within the tumor microenvironment (e.g., block inhibitory receptor engagement (e.g., PD-Ll/PD-1 interactions), deplete or inhibit Tregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes such as IDO, or reverse/prevent T cell anergy or exhaustion) and agents that trigger innate immune activation and/or inflammation at tumor sites.
  • agonistic agents that ligate positive costimulatory receptors e.g., blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that increase systemically the frequency
  • the immuno-oncology agent is a PD-1 antagonist, such as an antagonistic PD-1 antibody.
  • PD-1 antibodies include, for example, OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514;
  • the immuno-oncology agent is a CD137 (4-1BB) agonist, such as an agonistic CD137 antibody.
  • Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (W012/32433).
  • the immuno-oncology agent is a GITR agonist, such as an agonistic GITR antibody.
  • GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06/105021, WO09/009116) and MK-4166 (WOl 1/028683).
  • the immuno-oncology agent is a CD40 agonist, such as an agonistic CD40 antibody.
  • the immuno-oncology agent is a CD40 antagonist, such as an antagonistic CD40 antibody.
  • Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • a compound of the present invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or di calcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.
  • Optically active forms may be prepared by resolution of racemic forms or by synthesis from optically active starting materials. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. When enantiomeric or diastereomeric products are prepared, they may be separated by conventional methods, for example, by
  • alkoxy refers to an -O-alkyl group.
  • C ⁇ alkoxy (or alkyloxy), is intended to include Ci, C 2 , C3, C4, C5, and C alkoxy groups.
  • Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and i-butoxy.
  • alkylthio or “thioalkoxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge; for example methyl-S- and ethyl-S-.
  • cycloalkyl refers to cyclized alkyl groups.
  • C3-6 cycloalkyl is intended to include C3, C4, C5, and C cycloalkyl groups.
  • Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl.
  • Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl”.
  • cycloalkenyl refers to cyclized alkenyl groups.
  • C 4- 6 cycloalkenyl is intended to include C 4 , C5, and Ce cycloalkenyl groups.
  • aromatic heterocyclic group or "heteroaryl” is intended to mean stable monocyclic and poly cyclic aromatic hydrocarbons that include at least one heteroatom ring member such as sulfur, oxygen, or nitrogen.
  • Heteroaryl groups include, without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4- thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, benzodi
  • EWG electron withdrawing group
  • EWGs include, but are not limited to, CF 3 , CF 2 CF 3 , CN, halogen, haloalkyl, N0 2 , sulfone, sulfoxide, ester, sulfonamide, carboxamide, alkoxy, alkoxyether, alkenyl, alkynyl, OH, C(0)alkyl, CO2H, phenyl, heteroaryl, -O-phenyl, and -O- heteroaryl.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, gly colic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxy maleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric
  • organic acids such as acetic, propionic, succinic, gly colic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxy maleic, phenylace
  • compounds of formula I may have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent (i. e. , a compound of formula I) is a prodrug within the scope and spirit of the invention.
  • a prodrug within the scope and spirit of the invention.
  • Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see:
  • esters of compounds of formula I include C ⁇ alkyl, C ⁇ alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, C i- alkanoyloxy-C ⁇ alkyl (e.g. , acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl),
  • the present invention is intended to include all isotopes of atoms occurring in the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • the isotopes of hydrogen can be denoted as 3 ⁇ 4 (hydrogen), 2 H (deuterium) and 3 ⁇ 4 (tritium). They are also commonly denoted as D for deuterium and T for tritium.
  • CD3 denotes a methyl group wherein all of the hydrogen atoms are deuterium.
  • Isotopes of carbon include 13 C and 14 C.
  • the term "pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.
  • bases include, but are not limited to, alkali metals (e.g. , sodium) hydroxides, alkaline earth metals (e.g. , magnesium), hydroxides, ammonia, and compounds of formula NW ⁇ 4 + , wherein W is Ci-4 alkyl, and the like.
  • salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable.
  • salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
  • the compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis.
  • the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety by reference.
  • the compounds of this invention may be prepared using the reactions and techniques described in this section.
  • the reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being affected.
  • all proposed reaction conditions including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and work up procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
  • Deprotection may be accomplished by treatment with tetrabutylammonium fluoride in a solvent such as THF or other means known to one skilled in the art to afford compounds of formula iv.
  • a solvent such as THF or other means known to one skilled in the art to afford compounds of formula iv.
  • the reaction of compounds of formula iv with suitably substituted 3-aminopyridines (v, X halogen) in the presence of a catalyst such as Pd(PPh3)2Ch with an additive such as Cul in the presence of a base such as triethylamine in an appropriate solvent such as
  • Example 1A A mixture of Example 1A (4.2 g, 19.3 mmol), ethynyltrimethylsilane (2.28 g, 23.2 mmol), bis(triphenylphosphine)palladium(II) dichlororide (0.27 g, 0.39 mmol) and copper(I) iodide (0.15 g, 0.77 mmol) in TEA (20 mL, 143 mmol) was purged with nitrogen and heated to 76 °C for 2.5 h, and then cooled to room temperature. The mixture was filtered through a short silica gel column, eluting with EtOAc.
  • Example IB (2.89 g, 94%) as a light yellow solid.
  • Example IE (12.5 mg, 31%) as a white solid.
  • Example 4 was prepared from Example ID and 2-fluoro-5-iodopyridine by the general methods shown for Example 1.
  • Example 8 was prepared from Example ID and 2-bromopyrimidine by the general methods shown for Example 1.
  • Example 9 was prepared from Example ID and 5-bromo-2-chloropyridine by the general methods shown for Example 1.
  • Example 10 was prepared from Example ID and 2,3-difluoro-5-iodopyridine by the general methods shown for Example 1.
  • Example 12 was prepared from Example ID and 5-bromopicolinonitrile by the general methods shown for Example 1.
  • MS (ES): m/z 355 [M+H] + ; 3 ⁇ 4 NMR (500 MHz, DMSO-de) ⁇ ppm 10.70 (br. s., 1H), 8.84 (s, 1H), 8.58 (br. s., 1H), 8.41 (br.
  • Example 14 may also be prepared by the alternative Method B:
  • Example 15
  • Example 17 was prepared from Example ID and 6-bromoisoquinoline by the general methods shown for Example 1.
  • Example 20 was prepared from Example ID and 5-bromo-lH-indole by the general methods shown for Example 1.
  • MS (ES): m/z 368 [M+H] + ; 3 ⁇ 4 NMR (500 MHz, DMSO-de) ⁇ ppm 11.33 (br.
  • Example 21 was prepared from Example ID and 8-bromoquinoline by the general methods shown for Example 1.
  • Example 22 was prepared from Example ID and 6-bromoquinoline by the general methods shown for Example 1.
  • Example 25 was prepared from Example ID and 2-bromo-5- (methylsulfonyl)pyridine by the general methods shown for Example 1.
  • Example 26 was prepared from Example ID and 2-bromo-5-methoxy pyridine by the general methods shown for Example 1.
  • MS (ES): m/z 360 [M+H] + ; 3 ⁇ 4 NMR (500 MHz, DMSO-de) ⁇ ppm 13.40 (br.
  • Example 27 was prepared from Example ID and 5-bromo-2-methoxypyrimidine by the general methods shown for Example 1.
  • Example 28 was prepared from Example ID and 2-bromo-4-methoxy pyridine by the general methods shown for Example 1.
  • Example 32 was prepared from Example ID and 2-bromo-4-chloropyridine by the general methods shown for Example 1.
  • Example 33 was prepared from Example ID and 6-bromo-3-chloro-2- methylpyridine by the general methods shown for Example 1.
  • Example 34 A was prepared from Example IB and 2-bromo-6-fluoropyridin-3- amine by similar methods as shown for Example 1C.
  • Example 34B was prepared from Example 34A by methods similar to those shown for Example ID.
  • Example 34 was prepared from Example 34B and 2-bromo-6-chloropyridine by the general methods shown for Example 1.
  • Example 36 was prepared from Example 34B and 5-iodo-2-methoxypyridine by the general methods shown for Example 1.
  • Example 38A was prepared from Example IB and 2-bromo-5-fluoropyridin-3- by the methods shown for Example 1 C.
  • Example 38 was prepared from Example 38B and 2-bromo-6-chloropyridine by the general methods shown for Example 1.
  • Example 39 was prepared from Example 38B and 2-bromo-5-methoxy pyridine by the general methods shown for Example 1.
  • Example 40 was prepared from Example 38B and 5-bromo-2-methoxypyridine by the general methods shown for Example 1.
  • Example 41 A was prepared from Example IB and 2-bromo-5-chloropyridin-3- amine by the methods similar to those shown for Example 1C.
  • Example 41B was prepared from Example 41 A by the methods similar to those shown for Example ID.
  • Example 41 was prepared from Example 41 B and 2-bromo-6-chloropyridine by the general methods shown for Example 1.
  • Example 42 was prepared from Example 41 B and 2-bromo-5-fluoropyridine by the general methods shown for Example 1.
  • Example 43 was prepared from Example 41B and 5-bromo-2-methoxypyridine by the general methods shown for Example 1.
  • Example 47 was prepared from Example 41 B and 2-bromo-5-methoxy pyridine by the general methods shown for Example 1.
  • Example 48A was prepared from Example IB and 2-bromo-5-methoxypyridin-3- amine by methods similar to those shown for Example 1C.
  • Example 48B was prepared from Example 48A by methods similar to those shown for Example ID.
  • Example 49 was prepared from Example 48B and 2-bromo-5-fluoropyridine by the general methods shown for Example 1.
  • Example 51 was prepared from Example 48B and 6-bromo-3-fluoro-2- methylpyridine by the general methods shown for Example 1.
  • Example 14 To a solution of Example 14 (38 mg, 0.106 mmol) in MeOH (8 mL) was added IN NaOH (1.057 mL, 1.057 mmol). The mixture was then heated at 80 °C for 1.5 h, and then concentrated. The solid residue was suspended in water, collected by filtration, and dried to give the title product (27.4 mg, 80%) as a white solid.
  • Example 52 To a solution of Example 52 (12.1 mg, 0.038 mmol) and TEA (10.6 ⁇ , 0.076 mmol) in THF (0.6 mL) was added a solution of cyclopropanecarbonyl chloride (6.8 mg, 0.065 mmol) in THF (70 ⁇ ). The reaction was stirred for 2 h, and then concentrated NH4OH (1 drop) was added. The resulting reaction mixture was stirred at room temperature overnight.
  • the mixture was diluted with DMF and purified by preparative HPLC (Column: Waters XBridge C I 8, 19 x 200 mm, 5- ⁇ particles; Mobile Phase A: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95 :5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 10-55% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.) to give Example 53 (4.0 mg, 23%).
  • Example 14 To a solution of Example 14 (12 mg, 0.033 mmol) in DMF (0.5 mL) was added CS2CO3 (21.76 mg, 0.067 mmol), followed by a solution of methyl iodide (2.088 ⁇ , 0.033 mmol) in DMF (0.5 mL).
  • Example 55B was prepared from 55A by methods similar to those shown for Example ID.
  • Example 55 was prepared from Example 55B and 2-bromo-6-chloropyridine by the general methods shown for Example 1.
  • Example 56B (2.45 g, 8.77 mmol) and Example IB (1.544 g, 9.64 mmol) in DMF (18 mL) were added Cul (0.134 g, 0.701 mmol) and TEA (12.2 mL, 88 mmol). The reaction mixture was purged with nitrogen, followed bythe addition of PdCl 2 (PPh 3 )2 (0.369 g, 0.526 mmol). The resulting mixture was heated at 78 °C for 2 h under nitrogen. The reaction mixture was then cooled to room temperature and diluted with ethyl acetate and saturated aqueous NaHC0 3 solution.
  • Example 58A was prepared from Example 56E and 2-aminopropane-l,3-diol by similar method shown for Example 56F. .
  • Example 58B was prepared using similar methods as those shown for Example 56G.
  • MS (ES): m/z 482.0, 484.0 [M+H] + .
  • Example 58 was prepared from Example 58B by the general method shown for Example 56 ⁇ .
  • MS (ES): m/z 51 1.2 [M+H] + .
  • Example 59 was prepared from Example 58C by similar methods shown for Example 57.
  • reaction mixture was stirred at room temperature for 5 h. The reaction mixture was then concentrated in vacuo to a small volume. To the reaction mixture was added IN NaOH solution and ethyl acetate. The organic layer was separated and washed with a saturated NaHC0 3 solution, dried over MgS0 4 , and then filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluting with 15% ethyl acetate in hexane to give the desired product as a white solid (1.65 g, 51 %).
  • Example 61 A (1.55 g, 7.47 mmol) and Example IB (1.257 g, 7.85 mmol) in DMF (6 mL) were added Cul (0.142 g, 0.747 mmol) and TEA (10.41 mL, 74.7 mmol). The reaction mixture was purged with nitrogen, and treated with
  • Example 61B To a suspension of Example 61B (0.95 g, 3.31 mmol) in DCE (12 mL) at ice bath temperature was added TEA (1.62 mL, 11.60 mmol), followed by the addition of trifluoroacetic anhydride (0.74 mL, 5.30 mmol) slowly. The reaction mixture was stirred at 0 °C for 20 min. To the mixture was added more TEA (1.0 mL) and trifluoroacetic anhydride (0.45 mL) and the reaction mixture was stirred at 0 °C for another 40 min. The reaction mixture was quenched with a cold saturated NaHC0 5 solution and the resulting mixture was extracted with ethyl acetate (2x).
  • Example 61C A mixture of Example 61C (30 mg, 0.078 mmol), CS2CO3 (77 mg, 0.235 mmol) and 2-bromo-5-fiuoropyridine (17.93 mg, 0.102 mmol) in acetonitrile (2 mL) in a sealed tube was purged with nitrogen, and treated with Pd(PPh3)4 (9.06 mg, 7.84 ⁇ ). The reaction mixture was heated at 100 °C for 1.5 h and then cooled to room temperature. The reaction mixture was diluted with MeOH and ethyl acetate and filtered. The filtrate was concentrated in vacuo.
  • Example 62 was prepared from Example 61 C and 2-bromo-5-methoxy pyridine by the general method shown for Example 61.
  • Example 63 was prepared from Example 61 C and 2-bromo-5-chloropyridine by the general method shown for Example 61.
  • Example 64 was prepared from Example 61 C and 2-bromo-6-fluoropyridine by the general method shown for Example 61. .
  • Example 65 was prepared from Example 41 B and 2-bromo-6-methoxy pyridine by the general methods shown for Example 1.
  • Example 66 was prepared from Example 41 B and 2-bromo-6-methylpyridine by the general methods shown for Example 1. .
  • Example 67 was prepared from Example 41 B and (6-bromopyridin-2-yl)methanol by the general methods shown for Example 1. .
  • Example 68 was prepared from Example 41B and 2-((6-bromopyridin-2- yl)amino)ethanol by the general methods shown for Example 1.
  • Example 56C To a suspension of Example 56C (0.2 g, 0.557 mmol) in DCE (4 mL) and diethyl ether (10 mL) was added CaCC (0.223 g, 2.230 mmol) at ice bath temperature. To the reaction mixture was added TFAA (0.17 mL, 1.226 mmol) slowly and the reaction mixture was stirred at ice bath temperature for 2 h. To the reaction mixture was added cold water and ethyl acetate. The organic layer was separated and washed with brine and dried over MgS0 4 . The mixture was filtered and the filtrate was concentrated in vacuo.
  • Example 69 was prepared from Example 69A and 2-bromo-5-fluoropyridine by the general methods shown for Example 1.
  • Example 70 was prepared from Example 69A and 2-bromo-5-chloropyridine by the general methods shown for Example 1.
  • Example 72A To a suspension of Example 72A (60 mg, 0.177 mmol) in DCE (3 mL) were added acetoxyacetyl chloride (0.06 mL, 0.54 mmol) and TEA (0.1 mL, 0.71 mmol). The reaction was stirred at room temperature for 2 h. To the reaction mixture was added 0.5 mL of an ammonia hydroxide solution and the mixture was stirred at room temperature for 1 h. The resulting reaction mixture was concentrated in vacuo.
  • Example 72A To a suspension of Example 72A (1 15 mg, 0.338 mmol) in DCE (7 niL) were added chloroacetyl chloride (0.14 mL, 1.70 mmol) and TEA (0.25 mL, 1.70 mmol) slowly. The reaction was stirred at room temperature for 1 h. To the reaction mixture was added 1 mL of ammonia hydroxide solution and the mixture was stirred at room temperature for 0.5 h. The reaction mixture was then diluted with CHC1 3 : 2-propanol
  • Example 74A 35 mg, 0.084 mmol
  • acetonitrile 2 mL
  • morpholine 0.074 mL, 0.841 mmol
  • Ag 2 0 39.0 mg, 0.168 mmol
  • Example 75 was prepared from Example 74A and 2-aminoethanol by the general methods shown for Example 74.
  • Example 76A (80 mg, 0.283 mmol) in Ether:DCM (1 : 1) (4 mL) was added dropwise a solution of 2,2,2-trifluoroacetic anhydride (0.039 mL, 0.283 mmol) in DCM (1 mL) at -10 °C. The reaction mixture was stirred for 30min at -10 °C to 0 °C. The reaction mixture was then diluted with EtOAc, washed with water, and then with satutared aqueous NaCl, dried with MgSCn and concentrated to yield Example 76B (90 mg, 0.238 mmol, 84 % yield) as an off white solid which was used for the next step without further purification.
  • Example 76 was preapared from Example 76B and 5-bromo-2-methoxypyridine following the general method for Example 1.
  • Example 77 was preapared from Example 76B and 2-bromo-6-chloropyridine following the general method for example 1.
  • the reaction mixture was concentrated in vacuo. To the residue was added 20 mL of iPrOH, the mixture was sonicated and the solid was filtered and washed with iPrOH. The resulting solid was triturated with CH2CI2 and collected by filtration. The filtrate was concentrated and the residue was triturated with CH2CI2 to obtain a second crop of the title compound. Both solids were combined to obtain 2 g of yellow solid. The filtrate was further concentrated in vacuo and the residue was purified by column chromatography on S1O2 (gradient hexane/EtOAc) to obtain 640 mg of the title compound, total 2.64 g (93% yield) as a yellow solid.
  • Example 78A 300 mg, 0.91 mmol
  • Zn(CN) 2 106 mg, 0.91 mmol
  • DMF dimethyl methoxylate
  • PdCk dppf
  • Pd2dba3 80 mg, 0.087 mmol
  • the reaction mixture was again purged with N2 and heated at 85 °C for 6 h.
  • the reaction mixture was partially concentrated in vacuo and the residue was passed through a column of S1O2 (gradient CH2CI2 to 10% MeOH in CH2CI2) to obtain the title compound (135 mg, 0.487 mmol, 54 % yield) as a yellow solid.
  • MS (ES): m/z 278 [M+H] + ; 3 ⁇ 4 NMR (400 MHz,
  • Example 78B A mixture of Example 78B (530 mg, 1.911 mmol), CS2CO3 (685 mg, 2.103 mmol) and Pd(Ph3P)4 (110 mg, 0.096 mmol) in 12 mL DMF was purged with ⁇ 2 and the mixture was heated 150 °C for 20 minutes, and then cooled to room temperature. The reaction mixture was partially concentrated in vacuo, and the residue was mixed with 15 mL
  • Example 78C 600 mg, 2.164 mmol
  • DMF 15 mL
  • N-iodosuccinimde 487 mg, 2.164 mmol
  • the reaction mixture was partially concentrated in vacuo, and the residue was triturated with water and the solid was filtered to obtain the title compound (620 mg, 1.538 mmol, 71.1 % yield) as a light brown solid.
  • MS (ES): m/z 403.9
  • Example 78D A mixture of Example 78D (35 mg, 0.087 mmol), 2-methoxy-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine(30.6 mg, 0.130 mmol) and 0.2 mL 3M K3PO4 in DMF (2 mL) was purged with ⁇ 2. The mixture was treated with PdCl2(dppf) (25.4 mg, 0.035 mmol), purged with ⁇ 2 and heated at 80 °C for 60 min. The reaction mixture was concentrated to a volume of 1 mL and 3 mL MeOH was added.
  • Example 78 A mixture of Example 78 (50 mg, 0.130 mmol) and 20% Pd(OH)2 on carbon (10 mg) in MeOH (12 mL) was stirred under 1 atm of H2 at room temperature. After 4 h additional 20% Pd(OH)2 on carbon (20 mg) was added and stirring was continued under 1 atm H2.
  • Example 80 and Example 81 were prepared following similar procedures as described in Examples 78 and 79.
  • Example 72A To a solution of Example 72A (0.45 g, 1.18 mmol) in DMF (8 mL) were added CS2CO3 (0.85 g, 2.59 mmol) and ⁇ -toluenesulfonyl chloride (0.22 mL, 1.18 mmol). The reaction mixture was stirred at room temperature over night. To the reaction mixture was added ethyl acetate and a saturated NaHC0 3 solution. The organic layer was extracted with ethyl acetate (2x) and the combined organic layers were washed with saturated NaHC0 3 solution, dried over MgS0 4 and filtered. The filtrate was concentrated in vacuo.
  • Example 82A To a suspension of Example 82A (50 mg, 0.093 mmol) in THF (1 mL) was added methyl iodide (0.017 mL, 0.280 mmol) in DMF (0.6 mL) and CS2CO3 (61 mg, 0.187 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then diluted with ethyl acetate and saturated NaHC0 3 solution. The organic layer was separated and dried over MgS0 4 and filtered. The filtrate was concentrated in vacuo to give the desired product, which was used in the next step without purification.
  • Example 83A was prepared from Example IB and 2,5-dibromopyridin-3-amine by methods similar to those shown for Example 1C.
  • Example 83 was prepared from Example 83B and 2-bromo-5-methoxy pyridine by the general methods shown for Example 1.
  • Example 52 To a suspension of Example 52 (28.8 mg, 0.091 mmol) in CH2CI2 (2 mL) was added TEA (0.038mL, 0.272 mmol) and methyl chloroformate (0.014 mL, 0.182 mmol). The mixture was stirred at room temperature overnight, and then MeOH (1 mL) and concentrated NH4OH (1 drop) were added. The resulting reaction mixture was stirred at room temperature ovemight.
  • Example 84 (10.5 mg, 31 %).
  • Example 72A To a suspension of Example 72A (68 mg, 0.20 mmol) in DCE (3 mL) were added methyl chloroformate (0.04 mL, 0.52 mmol) and 4-methylmorpholine (0.13 mL, 1.20 mmol). The reaction mixture was stirred at room temperature for 1 h. Additional methyl chloroformate (0.04 mL, 0.52 mmol) and 4-methylmorpholine (0.13 mL, 1.201 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for another 0.5 h. To the mixture was added ammonium hydroxide (0.6 mL) and MeOH (3 mL). The resulting mixture was stirred at room temperature for 20 h.
  • reaction mixture was then diluted with a saturated NaHC0 3 solution and CHC1 3 : 2-propanol (2.5 : 1). The layers were separated and the aqueous layer was extracted with CHC1 3 : 2- propanol (2.5 : 1). The combined organic layers were dried over MgS0 4 and filtered. The filtrate was concentrated in vacuo to give a yellow solid. To the extract was added DCM, the mixture was sonicated and then filtered to give the desired product as a yellow solid (35 mg, 42%).

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Abstract

L'invention concerne de manière générale des composés de formule (I) qui modulent l'activité du TGFβR-1 et du TGFβR-2, des compositions pharmaceutiques contenant lesdits composés et des procédés de traitement de troubles prolifératifs et de troubles liés à une dérégulation de l'apoptose, tels que le cancer, à l'aide des composés de l'invention.
PCT/US2015/067252 2014-12-22 2015-12-22 Antagonistes des récepteurs tgfβ WO2016106266A1 (fr)

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WO2018086609A1 (fr) 2016-11-14 2018-05-17 江苏恒瑞医药股份有限公司 Dérivé de 3,4-bipyridyle pyrazole, procédé de préparation et application médicale associés
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CN112694477B (zh) * 2019-10-22 2024-02-06 四川科伦博泰生物医药股份有限公司 吡唑并环类化合物，包含其的药物组合物，其制备方法及其用途
CN110885329B (zh) * 2019-12-16 2020-12-15 诚达药业股份有限公司 一种1,7-萘啶衍生物的合成方法
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